What are. Immunotherapy. Side Effects?

Transcription

1 Immunotherapy Side Effects What are Immunotherapy Side Effects? Let us answer some of your questions. ESMO Patient Guide Series based on the ESMO Clinical Practice Guidelines esmo.org

2 Immunotherapy-related side effects Immunotherapy-related side effects and their management An ESMO guide for patients Patient information based on ESMO Clinical Practice Guidelines This guide has been prepared to help you, as well as your family, friends and caregivers, better understand immunotherapy-related side effects and their management. It contains information on the most common toxicities associated with modern immunotherapies (known as checkpoint inhibitors ), how your oncology team will manage these symptoms, and a few strategies you can use yourself to minimise their effects. The medical information described in this document is based on the ESMO Clinical Practice Guideline for management of toxicities from immunotherapy, which is designed to help clinicians with the diagnosis, treatment and follow-up of these events. All ESMO Clinical Practice Guidelines are prepared and reviewed by leading experts using evidence gained from the latest clinical trials, research and expert opinion. The information included in this guide is not intended as a replacement for your doctor s advice. Your doctor knows your full medical history and will help guide you regarding the best treatment for you. This guide has been developed and reviewed by: Representatives of the European Society for Medical Oncology (ESMO): John Haanen; Karin Jordan; Francesca Longo; Jean-Yves Douillard; Svetlana Jezdic; Claire Bramley Representatives of the European Oncology Nursing Society (EONS): Anita Margulies; Ada Kinneally Representative from Lung Cancer Europe: Regine Deniel Ihlen Representative from Women Against Lung Cancer: Stefania Vallone Representative from International Kidney Cancer Coalition: Rachel Giles Representative from Melanoma Patient Network Europe and MelanomeFrance: Gilliosa Spurrier 2

3 WHAT S INSIDE ESMO Patients Guide 2 An ESMO guide for patients 4 Immunotherapy-related side effects: A summary of key information 6 The immune system and cancer 10 The concept of immuno-oncology 13 How does modern immunotherapy differ from chemotherapy and tumour-targeted drugs? 15 What are the side effects of immunotherapy? 20 How will immunotherapy-related side effects be managed? 25 References 26 Glossary 3

4 Immunotherapy-related side effects Immunotherapy-related side effects: A summary of key information The immune system and cancer The immune system consists of many different components in the body. Some act as physical/chemical barriers (skin, cornea, membranes in the respiratory tract, gastrointestinal tract, urinary tract and reproductive tract). Others make and/or circulate specialised immune cells (the lymphatic system, bone marrow, spleen and thymus gland). The role of the immune system is to defend the body against threats, including microorganisms (bacteria, viruses, fungi) and cancer cells. After the physical/chemical barriers of the body, the next line of defence comprises white blood cells (leucocytes) that look for, and attack, microorganisms or abnormal cells (including cancer cells). T cells are white blood cells that play an important part in the acquired immune response in which each T cell learns, remembers and is specific to a particular antigen. T cells are activated via a lock and key mechanism enabling them to recognise, attack and kill cancer cells. Many cancers are probably prevented by immune system surveillance and destruction of abnormal cells, but cancer cells can outwit the immune system in various ways. The concept of immuno-oncology While chemotherapy or tumour-targeted drugs directly affect the growth and proliferation of tumour cells, immuno-oncological drugs harness the body s natural anti-cancer immune response to attack and destroy the cancer. Manipulation of immune checkpoints is at the leading edge of immuno-oncology. Immune checkpoints are designed to turn off the immune response to prevent autoimmunity and damage to healthy cells, but cancer hijacks these mechanism by deactivating T cells once they have recognised the cancer, preventing attack and destruction of a cancer cell. Checkpoint inhibitors such as CTLA-4 inhibitors and PD-1 pathway inhibitors (two types already available in the clinic) or PD-L1 inhibitors (one type available in the clinic) prevent this deactivation and increase the body s anti-tumour immune response. How does modern immunotherapy differ from chemotherapy and tumour-targeted drugs? Chemotherapy involves the use of one or more drugs to destroy tumour cells, based on the fact that these cells typically divide rapidly; side effects are caused by damage to normal cells, especially those that also divide rapidly, such as cells in the bone marrow, hair follicle and gastrointestinal tract. 4

5 ESMO Patients Guide Tumour-targeted drugs specifically act against molecular targets in cancer cells identified by tissue and blood samples. These drugs are used to treat some types of cancer in selected patients based on molecular characteristics of their tumours. In general, it is expected that these drugs have less side effects on normal cells than chemotherapy, but side effects from tumour-targeted drugs could also be substantial and depend largely on what each drug targets. Because modern immunotherapy with checkpoint inhibitors blocks the body s natural safeguards that prevent immune overactivation, it can also affect normal tissues and cause autoimmune side effects. These comprise a different spectrum of events compared with those associated with chemotherapy and tumour-targeted drugs, and require different management strategies. What are the side effects of immunotherapy? Immune-related side effects arising from treatment with checkpoint inhibitors can affect any organ or tissue, but most commonly affect the skin, colon, lungs, liver and endocrine organs (such as the pituitary gland or thyroid gland). Most of these side effects are mild to moderate and reversible if detected early and addressed appropriately, so the most important action you can take is to tell your doctor or oncology team of any new or worsening symptoms, or any symptoms that are worrying you. Side-effects of checkpoint inhibitor treatment typically appear within a few weeks or months of starting treatment, but they can arise at any time during treatment as early as days after the first infusion, but sometimes as long as 1 year after treatment has finished. The most common side effects for CTLA-4 inhibitors and PD-1/PD-L1 pathway inhibitors are skin symptoms (like rash and itching), while gastrointestinal symptoms (like diarrhoea) seem to be more common with CTLA-4 inhibitors and lung symptoms and thyroid gland dysfunction seem to be more common with PD-1/PD-L1 pathway inhibitors. How will immunotherapy-related side effects be managed? Checkpoint inhibitor-related side effects all are managed according to some basic common principles: Grade 1 (mild severity) or Grade 2 (moderate severity) events generally are managed symptomatically, without interrupting or permanently stopping treatment. Patients with persistent Grade 2 symptoms may need to skip one or more treatment doses (as well as receiving symptomatic treatment), until their symptoms have improved. For patients with Grade 3 (severe) or Grade 4 (very severe) symptoms, treatment will typically be discontinued and referral to a specialist for example, a dermatologist for severe skin symptoms will usually be made. Oral or intravenous corticosteroids, or other immunosuppressive drugs, are used for severe or persistent side effects; their use does not appear to compromise the efficacy of treatment with checkpoint inhibitors. If you have to permanently stop treatment with an immune checkpoint inhibitor, this should not negatively affect how your cancer responds. 5

6 Immunotherapy-related side effects The immune system and cancer What is the immune system? The human immune system comprises the lymphatic system, bone marrow, spleen and thymus gland; collectively, they produce and/or circulate specialised immune cells. The skin, cornea of the eye, and membranes lining the respiratory tract, gastrointestinal tract, urinary tract and reproductive tract act as physical/chemical barriers against microorganisms such as bacteria and viruses. The bone marrow and thymus gland are primary lymphoid organs where white blood cells are produced and/or multiply. White blood cells are a group of immune cells pivotal to effective immunity. s t ra Ga tro ct Skin in t e s ti n al The immune system consists of many different components in the body, some of which act as physical/chemical barriers (skin, cornea, membranes in the respiratory tract, gastrointestinal tract, urinary tract and reproductive tract) while others make and/or circulate specialised immune cells (the lymphatic system, bone marrow, spleen and thymus gland). 6

7 ESMO Patients Guide What is the function of the immune system? The immune system defends the body against infections and cancer The role of the immune system is to defend the body against foreign or dangerous invaders, including microorganisms (bacteria, viruses, fungi) and cancer cells. To do this effectively, the immune system must be able to differentiate between self (normal cells belonging to the individual) and non-self (abnormal cells or organisms/particles that are foreign to the individual). A normal immune response comprises: 1. Recognition of potentially harmful antigens. These may originate from outside the body, e.g. from invading bacteria, or from within the body, e.g. normal cells that have mutated and potentially could or have become malignant. 2. Activation and mobilisation of cellular and antibody defences. 3. Attack against the invader or abnormal cell. 4. Termination of the attack once the threat has been counteracted. Besides the physical/chemical barriers of the body, another line of defence comprises white blood cells (leucocytes) that travel through the bloodstream and into tissues and organs looking for, and attacking, microorganisms or abnormal cells. There are various different types of white blood cells that perform different functions, ranging from directly attacking and killing invaders or abnormal cells, to releasing special substances that enhance the immune response by other cells. 7

8 Immunotherapy-related side effects There are many different types of leucocytes each having a specific function in the immune response. The immune response consists of two phases: Innate immunity: this is quick but not specific a previous encounter with the invader or abnormal cell is not needed for this response. The innate response is activated in response to potentially harmful pathogens such as bacteria and viruses. Acquired immunity: this is slower but specific the immune system learns to recognise the invader/ abnormal cell and can attack it more efficiently the next time it encounters it. The process of acquired immunity is the basis for vaccinations. The acquired immune system has been manipulated for its therapeutic benefit in cancer management and is therefore explained in more detail below. The primary types of immune cells involved in the acquired immune response are B cells and T cells, which work together to destroy invaders or abnormal cells. In order to recognise foreign organisms/particles or abnormal cells, T cells require the help of specialised cells collectively called antigen-presenting cells which ingest the invader or abnormal cell and break it up into smaller pieces so that antigens of the invader or abnormal cell become visible to T cells. 8

9 ESMO Patients Guide 1. T cells can recognise antigens only after these have been processed by antigen-presenting cells, combined with major histocompatibility complex (MHC) and presented to a specialised T cell receptor (TCR) located on the surface of the T cell. 2. Presented in this way, the antigen/mhc combination acts like a key which fits the TCR lock, activating the T cell (a process called priming ); activated T cells proliferate and differentiate into antigen-specific T cells and a small pool of memory cells (which will remember the specific antigen if encountered again, thereby ensuring a more effective immune response). 3. Activated cytotoxic T cells attack infected or cancer cells carrying the specific antigen that the T cells recognise, and kill them. How does the immune system respond to cancer? Many cancers are prevented by immune system surveillance and destruction of abnormal cells, without the person being aware of this. Cancer cells are clever, however, and have developed the ability to outwit or hide from the immune system in one or more ways, including: Hiding their identity: a cancer cell can reduce the expression of tumour antigens on its surface, making it more difficult for the immune system to identify it as being abnormal. Putting up a barrier: a cancer cell can express proteins on its surface that inactivate an immune cell. Influencing other cells: a cancer cell can influence cells close to it to release substances that suppress the immune response (and facilitate cancer cell proliferation and survival). Cancer cells can outwit the immune system in several ways 9

10 Immunotherapy-related side effects The concept of immuno-oncology In contrast to cancer therapies that directly affect the growth and proliferation of tumour cells such as chemotherapy or tumour-targeted drugs immuno-oncological drugs harness the body s natural anticancer immune response, boosting its ability to attack and destroy the cancer (Kamta et al., 2017). Immunooncological approaches fall into two main categories: Passive immunotherapy which facilitates and enhances the body s existing immune response; examples include checkpoint inhibitors. Active immunotherapy which directs the body s immune cells to recognise, attack and destroy cancer cells; examples include anti-cancer vaccines. Of these two approaches, the most successful so far is passive immunotherapy. Manipulation of immune checkpoints is at the leading edge of immuno-oncology. Immune checkpoints are the body s natural defence against autoimmunity; they are designed to turn off the immune response to prevent collateral damage to healthy cells, by deactivating (or in some instances, destroying) activated lymphocytes such as T cells once they have recognised, attacked and destroyed a cancer cell (or microorganism). Currently, the two types of checkpoint inhibitors that are commercially available in the clinic are: CTLA-4 inhibitors CTLA-4 is a specialised molecule that is produced by T cells during the early stages of their activation in lymphoid organs, whereupon it migrates to the cell surface and deactivates the T cell to prevent an excessive immune response (and unwanted autoimmunity). By blocking this deactivation, CTLA-4 inhibitors magnify the anti-tumour immune response (Boutros et al., 2016). PD-1 pathway inhibitors (PD-1/PD-L1 inhibitors) PD-1 is a specialised molecule that moderates the activity of T cells later in their response to cancer, once they have arrived at the tumour site. By preventing PD-1 (the lock ) from binding with PD-L1 (the key ), PD-1/PD-L1 inhibitors prolong and may even reinvigorate the anti-tumour immune response. PD-1/PD-L1 provide a necessary mechanism to minimise unwanted autoimmunity and damage to peripheral tissues once the immune cells have done their job, but cancer cells can hijack this mechanism by producing lots of keys themselves, thereby suppressing the immune response (Boutros et al., 2016). 10

11 ESMO Patients Guide A. T CELL PRIMING IN LYMPHOID ORGANS B. T CELL REACTIVATION IN TUMOUR ZONE MHC CD80/ CD28 CD86 TCR Signal 2 (activation) Signal 1 (recognition) APC CD80/ CD86 CTLA4 T cell Signal 3 (deactivation) CTLA-4 inhibitor MHC Signal 1 (recognition) TCR Signal 2 (deactivation) Early T cell activation Tumour cell PDL-1 PD-1 PD-1 inhibitor T cell T cell reactivation and proliferation CTLA-4 inhibitors and PD-1/PD-L1 inhibitors affect T cells at different stages in their immune actions and at different locations. CTLA-4 inhibitors work at an early stage during the early deployment of T cells and primarily facilitate their sustained activation and proliferation in lymphoid organs (A), while PD-1/PD-L1 inhibitors primarily delay the later phenomenon of T cell exhaustion due to prolonged exposure to high levels of tumour antigen in and around the cancer site (and may also reinvigorate exhausted T cells, B). Adapted by permission from Macmillan Publishers Ltd: [Nature Reviews Clinical Oncology] (Boutros, et al. Safety profiles of anti-ctla-4 and anti-pd-1 antibodies alone and in combination), copyright (2016). Checkpoint inhibitors magnify the body s natural immune response to cancer 11

12 Immunotherapy-related side effects Several CTLA-4 inhibitors and PD-1/PD-L1 inhibitors have been approved for clinical use in various types of cancer, and they and others are continually being tested in clinical trials for other cancers. All CTLA-4 inhibitors and PD-1/PD-L1 inhibitors available so far are monoclonal antibodies specialised, targeted proteins made in the laboratory that each bind to a specific molecule. They are all administered by injection/ intravenous infusion. Mostly, they are given as a single-agent treatment but sometimes, they can be combined with chemotherapy or each other (Haanen et al., 2017). DRUG TYPE CTLA-4 inhibitors PD-1 inhibitors (targeting the lock ) EXAMPLES Ipilimumab Nivolumab Pembrolizumab PD-L1 inhibitors (targeting the key ) Atezolizumab Avelumab Durvalumab Combination therapy Ipilimumab + nivolumab Approved drugs are those that have met the requirements of the regulatory authorities in a specific country or region to prove that they are effective and safe enough to be used in daily clinical practice. Drugs that have not been approved can still be given to patients who have enrolled in a clinical trial, since these patients will be monitored very closely. Sometimes, the clinical trial will form part of the evidence needed to get a drug approved. 12

13 ESMO Patients Guide How does modern immunotherapy differ from chemotherapy and tumour-targeted drugs? As with chemotherapy and tumour-targeted drugs, treatment with checkpoint inhibitors may also cause side effects but they are very different and require different management strategies Chemotherapy involves the use of one or more drugs to destroy tumour cells directly or stop cancer growth by inhibiting cancer cells ability to multiply. Chemotherapy is designed to affect cancer cells to a greater extent than normal cells, since cancer cells typically divide and multiply rapidly; however, this desired selectivity is not perfect, because normal cells also need to divide and multiply to replace themselves as they age and some normal cells also divide rapidly, such as cells in the bone marrow, those lining the gastrointestinal tract, and cells in the hair follicles. This is the reason for some of the common side effects from chemotherapy, such as hair loss, nausea and vomiting, reduced white blood cell counts (leucopaenia, neutropaenia), reduced red blood cell counts (anaemia), reduced platelet counts (thrombocytopaenia), diarrhoea and mucositis. Many of these side effects go away after chemotherapy ends and normal cells recover. Different types of chemotherapy drugs may produce different ranges of side effects. Tumour-targeted drugs are used for treatment of some cancer types in selected patients based on molecular characteristics of tumours determined by tissue and blood analysis. Tumour-targeted drugs can also cause side effects and their side effects profile depends largely on what the drug targets. The most common side effects from these drugs are diarrhoea, liver problems, skin problems, heart problems and high blood pressure. Because many of tumour-targeted drugs are quite new, it is still not known if they can cause longterm side effects. The side effects from treatment with checkpoint inhibitors are caused by a form of autoimmune reaction Unlike chemotherapy, which directly attacks tumour cells or tumour-targeted drugs that act against molecular targets in cancer cells, modern immunotherapy with checkpoint inhibitors works indirectly, by harnessing the patient s own immune system. Because it blocks the body s natural safeguards that prevent immune overactivation, however, immunotherapy can also affect normal tissues and cause side effects. 13

14 Immunotherapy-related side effects Checkpoint inhibitors can induce multiple immune-mediated changes that manifest as autoimmune side effects which are different to side effects associated with chemotherapy, and therefore require different management strategies. Drugs targeting the CTLA-4 and PD-1 pathways have slightly different side-effect profiles, although there is considerable overlap (June et al., 2017). Because immunotherapy drugs are new, the full range of their side effects is still not known, as well as it s not known how long after the treatment ends they may appear. 1. Tumor 2. Tumor cell death 4. Antigen presenting cell TILs Endolysosome Self-antigens Tumor mutant antigens 3. TCR MHCI TCR MHCII CD8 T cell CD4 T cell Activated tumour infiltrating lymphocytes (TILs) attack the tumour (1), which results in tumour cell death but also can cause damage to nearby normal cells (2). This process releases both tumour antigens from the cancer and some self-antigens from damaged normal cells (3), which are all ingested by antigen-presenting cells and used to activate more T cells (4). As a consequence of this mixing effect, some T cells are now going to recognise and attack normal tissues, causing autoimmune side effects. Adapted by permission from Macmillan Publishers Ltd: [Nature Medicine] (June, et al. Is autoimmunity the Achilles heel of cancer immunotherapy?), copyright (2017). 14

15 ESMO Patients Guide What are the side effects of immunotherapy? Side effects from treatment with checkpoint inhibitors are usually mild and reversible if reported and addressed early What symptoms should I look out for? Immune-related side effects (sometimes referred to as immune-related adverse effects or iraes) arising from treatment with checkpoint inhibitors can affect any organ or tissue, but most commonly affect the skin, colon, lungs, liver and endocrine organs (such as the pituitary gland or thyroid gland) (Haanen et al., 2017). Most immune-related side effects are mild to moderate and reversible if detected early and addressed appropriately, so you should always mention any symptoms that are worrying you as soon as you notice them to your oncology team (Champiat et al., 2016). They will be monitoring your progress and testing your blood for signs of any side-effects without obvious symptoms in their early stages. Because side-effects to checkpoint inhibitor treatment can arise at any time during treatment and sometimes also after treatment has finished your oncology team will also advise you to look out for any of the following symptoms, and to notify them accordingly: General: fatigue is a common side effect in patients treated with checkpoint inhibitors. Although its cause is poorly understood, it is important to exclude thyroid, pituitary, and other endocrine disorders. Skin: extensive rash or itching. Gastrointestinal: diarrhoea especially containing blood or mucus, or severe abdominal pain. Endocrine: fatigue, weight loss, nausea/vomiting, excessive thirst or appetite, excessive and/or frequent urination. Respiratory: shortness of breath, cough. Any of these less common symptoms: headache. confusion. muscle weakness or pain. numbness. painful or swollen joints. unexplained fever. tendency to bruise easily. loss of vision. 15

16 Immunotherapy-related side effects ENDOCRINE ORGANS e.g., overactive thyroid (hyperthyroidism) or underactive thyroid (hypothyroidism), or inflammation of pituitary gland (hypophysitis) LUNGS e.g., lung inflammation (pneumonitis) LIVER e.g., liver inflammation (hepatitis) SKIN e.g., rash, itching (pruritus), loss of pigment (vitiligo) GASTROINTESTINAL TRACT e.g., diarrhoea, colitis Side effects to checkpoint inhibitor therapy most often affect the skin, colon, endocrine organs (such as the pituitary gland or thyroid gland), liver and lungs. When are these side effects most likely to appear and how common are they? Immune-related side effects to checkpoint inhibitor therapy typically occur quite early mostly, within weeks to three months after treatment starts; however, first onset of side effects has been recorded as early as days after start to as long as one year after treatment has finished (Haanen et al., 2017). It is thought that the timeline for immune-related side effects mirrors the evolution of the body s immune response to cancer as it is boosted by checkpoint inhibitor therapy and eventual overactivation of this response that produces autoimmunity. Side effects from treatment with checkpoint inhibitors typically appear within weeks or a few months of starting treatment but can persist or first appear after treatment has finished 16

17 ESMO Patients Guide Most common iraes (>10%) Skin Gastrointestinal 15 Side effects from treatment with checkpoint 3 10 inhibitors typically appear within weeks or a few months of starting treatment but can persist or first appear after treatment has finished 0 Median Time (weeks) Less common iraes (<10%) Endocrine Hepatic Pulmonary Median Time (weeks) Side effects to PD-1 inhibitors typically appear between a few weeks and three months after treatment starts, although endocrine effects may take longer than others to manifest. (Weber J, et al: J Clin Oncol 35(7), 2017: Reprinted with permission. (2017) American Society of Clinical Oncology. All rights reserved.) Overall, the most common side effects for both types of drugs are skin symptoms, while gastrointestinal symptoms seem to be more common with CTLA-4 inhibitors and lung or thyroid symptoms seem to be more common with PD-1 inhibitors (Haanen et al., 2017). Liver side effects are less common and occur with roughly similar frequencies across both types of drugs. If you are treated with a combination of a CTLA-4 inhibitor and a PD-1 inhibitor, you will be more likely to get one or more side effects. AFFECTED ORGAN(S) CTLA-4 INHIBITORS PD-1/PD-L1 INHIBITORS Skin Rash 24% 15% Itching 25% 35% 13% 20% Gastrointestinal tract Diarrhoea 27% 54% Colitis 8% 22% Very low Lungs Cough/breathlessness 20% 40% Very low Pneumonitis 2% 4% Liver 5% 10% 5% 10% Endocrine organs Thyroid effects 1% 5% 5% 10% Hypophysitis 1% Very rare Estimated frequencies of the most common side effects to different types of checkpoint inhibitors vary but the most common events across both types of therapies involve symptoms in the skin. The majority of these side effects are mild and reversible (Adapted from Haanen et al., 2017). 17

18 Immunotherapy-related side effects The most common side effects involve the skin or gastrointestinal tract Doctors classify side effects from any cancer therapy by assigning each event a Grade, on a scale of 1 4, by increasing severity. Grade 1 side effects are considered to be mild, Grade 2 moderate, Grade 3 severe, and Grade 4 very severe. However, the precise criteria used to assign a grade to a specific side effect varies depending on which side effect is being considered. The aim is always to identify and address any side effect before it becomes severe, so you should always report any worrying symptoms to your oncology team as soon as possible. Two examples of how common side effects to checkpoint inhibitor therapy are graded are as follows (Haanen et al., 2017): Skin rash Grade 1, rash covering less than 10% of BSA (body surface area) with or without symptoms. Grade 2, rash covering 10% 30% of BSA with or without symptoms, affecting patient s ability to lead a normal life. Grade 3, rash covering over 30% of BSA with or without symptoms, affecting patient s ability to look after themselves. Grade 4, rash covering over 30% BSA with infection or other complications, requiring admission to hospital intensive care unit. 18

19 ESMO Patients Guide Diagram showing how doctors calculate body surface area when grading a rash caused by checkpoint inhibitor therapy. Haanen J, et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up, Annals of Oncology 2017;28 (suppl_4): iv119 iv142 doi: /annonc/mdx225. Reproduced with permission of Oxford University Press on behalf of the European Society for Medical Oncology. Diarrhoea Grade 1, fewer than three liquid stools per day more than before treatment started, patient feels well. Grade 2, between four and six liquid stools per day more than before treatment started, or abdominal pain, or blood in stool, or nausea, or night-time symptoms. Grades 3/4, over six liquid stools per day more than before treatment started, or symptoms occurring within 1 hour of eating; also applies to patients with Grade 1 or 2 stool frequency who also have other symptoms such as dehydration, fever, or a rapid heart rate. Other side effects will be graded in a similar way, but using criteria specifically relevant to each side effect, which may include laboratory values from blood tests for some of them. 19

20 Immunotherapy-related side effects How will immunotherapy-related side effects be managed? The principles for management of checkpoint inhibitor-related side effects generally are to manage Grade 1 or Grade 2 events by treating the symptoms, without interrupting or permanently stopping treatment. Patients with persistent Grade 2 symptoms may need to skip one or more treatment doses and also receive treatment for their symptoms, until their symptoms have subsided or resolved. For patients with Grade 3 or Grade 4 symptoms, treatment typically will be stopped and referral to a specialist will be arranged for example, a dermatologist for severe skin symptoms. The most important and effective strategy for managing side effects of checkpoint inhibitor therapy is early identification and intervention so you should always mention new or worsening symptoms to your doctor or oncology team Managed in outpatient/community setting Needs hospital admission and care Increasing intensity of treatment required Symptomatic therapy Oral steroids Stop treatment* * For some side effects, treatment can be restarted when they subside Referral to specialist Strong immunosupressive therapy Intravenous steroids started Grade 1 Grade 2 Grade 3 Grade 4 MILD MODERATE SEVERE VERY SEVERE Increasing grade of side effect The general principle for managing side effects from treatment with checkpoint inhibitors is firstly, to identify symptoms early and address them promptly with treatment for symptoms and possibly oral steroids. Only if symptoms worsen will you be admitted to hospital for treatment with intravenous steroids or other immunosuppressive therapy. Stéphane Champiat MD, PhD It is very important to note that side effects which lead to permanent discontinuation of treatment with checkpoint inhibitors are relatively infrequent, and early findings suggest that treatment with intravenous corticosteroids or stronger immunosuppressive drugs (for more severe side effects) does not negatively affect how your cancer will respond to immune checkpoint therapy. Likewise, evidence suggests that even if you have to permanently stop treatment with an immune checkpoint inhibitor, this will not compromise how your cancer responds (Champiat et al., 2016). 20

21 ESMO Patients Guide Management of most common immune-related side effects The table below provides a general guide regarding the typical management strategies for the most common immune-related side effects. However, this table is not intended as a replacement for your doctor s advice. Your doctor knows your full medical history and will help guide you regarding the best treatment for you. GRADE SYMPTOMS MANAGEMENT 1 Rash covering less than 10% of BSA with or without symptoms. Topical moisturising cream/ointment, oral or topical antihistamines for itching (if present) and/or topical corticosteroid cream (mild strength); checkpoint inhibitor treatment can continue. Skin side effects (rash/itching) 2 Rash covering 10% 30% of BSA with or without symptoms. Topical moisturising cream/ointment, oral or topical antihistamines for itching (if present) and/or topical corticosteroid cream (medium strength); checkpoint inhibitor treatment can continue. Self-help measures for Grade 1/2 (mild-to-moderate) symptoms are: avoid contact with skin irritants and exposure to sun 3 Rash covering less than 30% of BSA with or without symptoms. Topical moisturising cream/ointment, oral or topical antihistamines for itching (if present) and/or topical corticosteroid cream (high strength); plus intravenous corticosteroids; checkpoint inhibitor treatment will be withheld, but may be restarted if symptoms reduce to Grade 1 or mild Grade 2. 4 Rash covering over 30% BSA with infection or other complications. Intravenous corticosteroids and urgent specialist review; checkpoint inhibitor therapy must be discontinued permanently. continued overleaf 21

22 Immunotherapy-related side effects GRADE SYMPTOMS MANAGEMENT 1 Fewer than three liquid stools per day more than before treatment started, feeling well. Anti-diarrhoeal medication (e.g. loperamide), and oral electrolyte supplementation if required; checkpoint inhibitor treatment can continue. Gastrointestinal side effects (diarrhoea/colitis) 2 Four to six liquid stools per day more than before treatment started, or abdominal pain, or blood in stool, or nausea, or night-time symptoms. Oral corticosteroids and further tests (e.g. sigmoidoscopy/colonoscopy); checkpoint inhibitor treatment must be withheld until symptoms resolve. Self-help measures for Grade 1/2 (mild-to-moderate) diarrhoea/colitis are: drink plenty of fluids and avoid high-fibre/lactose diet 3 Grades 3/4, over six liquid stools per day more than before treatment started, 4 or symptoms occurring within 1 hour of eating; also applies to patients with Grade 1/2 stool frequency who have other symptoms such as dehydration, fever or a rapid heart rate. Hospital admission, intravenous corticosteroids and further tests (e.g. sigmoidoscopy/colonoscopy if not already done); if there is no response to corticosteroids, strong immunosuppressive drugs (e.g., infliximab) can be used checkpoint inhibitor therapy must be discontinued permanently. 1 None; based on findings from x-ray examination. Monitored every two to three days, tests to rule out other causes; checkpoint inhibitor treatment may be delayed. Lung side effects (pneumonitis) 2 Breathlessness, cough, chest pain. Antibiotics (if infection suspected), oral corticosteroids if no improvement on antibiotics or no infection found, further tests (including CT scan and bronchoscopy); checkpoint inhibitor treatment will be withheld. 3 Worsening symptoms, difficulty breathing. Hospital admission, intravenous corticosteroids, other stronger 4 immunosuppressive drugs if no improvement; checkpoint inhibitor treatment must be discontinued permanently. 22

23 ESMO Patients Guide GRADE SYMPTOMS MANAGEMENT 1 None; based on laboratory values from blood tests of liver enzyme levels. No immediate treatment necessary, blood tests repeated in one week s time; checkpoint inhibitor treatment can continue. Liver side effects (hepatitis) 2 None; based on laboratory values from blood tests of liver enzyme levels. 3 Grades 3/4, tiredness, feeling unwell, mild joint or muscle pains, decreased appetite/weight loss, nausea, itching, rash, diarrhoea, bloating; may have few or even no symptoms. Blood tests repeated every three days, further liver function tests done (if liver enzyme levels rising, oral corticosteroid treatment will be given); checkpoint inhibitor treatment will be withheld but may be restarted if symptoms improve (after corticosteroids have been gradually reduced). Oral or intravenous corticosteroids, depending on liver enzyme levels; checkpoint inhibitor therapy will be stopped. 4 Hospital admission, intravenous corticosteroids and specialist review; checkpoint inhibitor treatment must be discontinued permanently. Endocrine side effects Thyroid - For hyperthyroidism (usually transient and Grade 1 or 2), may be no symptoms if mild, various symptoms with increasing severity including nervousness, anxiety and irritability, mood swings, difficulty sleeping, persistent tiredness and weakness, sensitivity to heat, swelling in the neck from an enlarged thyroid gland, irregular and/or unusually fast heart rate (palpitations), twitching or trembling, weight loss. For hypothyroidism (usually Grade 1 or 2), may be no symptoms if mild, various symptoms with increasing severity including tiredness, sensitivity to cold, weight gain, constipation, depression, slow movements and thoughts, muscle aches and weakness, muscle cramps, dry and scaly skin, brittle hair and nails. For symptomatic hyperthyroidism, treatment is initiated with beta-blockers; checkpoint inhibitor therapy will be interrupted until symptoms resolve. For hypothyroidism, treatment is with long-term hormone replacement therapy (with thyroid hormones, depending on severity) and oral corticosteroids if thyroid gland inflamed; checkpoint inhibitor therapy may be interrupted until symptoms resolve. Blood tests will be done regularly for both conditions to monitor levels of thyroid hormones. Pituitary - For hypophysitis (usually Grade 1 or 2), no symptoms if mild, or any/all of various symptoms including headache, double vision, excessive thirst, production of large volumes of dilute urine, various hormonal imbalances (and related symptoms). Oral or intravenous corticosteroids and appropriate hormone replacement therapy (depending on severity and which set of hormones is affected); checkpoint inhibitor therapy may be continued during less severe (most) symptoms, but may be withheld for more severe symptoms. (Adapted from Haanen et al., 2017). 23

24 Immunotherapy-related side effects Management of rare side effects There are other side effects to checkpoint inhibitors which occur infrequently, but of which you should be aware, as follows (Haanen et al., 2017): Neurological symptoms according to an analysis of data from many clinical trials, these occur in approximately 4% 6% of people treated with CTLA-4 inhibitors or PD-1 inhibitors, or in up to 12% if treated with both types in combination, and manifests in a wide range of different ways (including muscle weakness, numbness and breathing difficulties); treatment for symptoms of Grade 2 or higher is based mainly on increasing strength oral or intravenous corticosteroids. Rheumatological symptoms mild or moderate muscle or joint pain occurs in 2% 12% of people treated with checkpoint inhibitors, more commonly with PD-1 inhibitors; treatment is mainly with oral analgesics (mild-to-moderate symptoms), low-dose oral corticosteroids (moderate symptoms), or for severe symptoms, consultation with a specialist and high-dose corticosteroids or intravenous immunosuppressive drugs may be necessary. Treatment with checkpoint inhibitors may need to be interrupted or stopped, depending on symptom severity. Kidney symptoms fewer than 1% of people treated with CTLA-4 inhibitors or PD-1 inhibitors experience kidney problems (although approximately 5% do so if treated with the two types of checkpoint inhibitors in combination); significant impairment of kidney function is treated with intravenous corticosteroids and specialist intervention, and may require checkpoint inhibitor treatment to be interrupted or stopped. Cardiac symptoms seen in fewer than 1% of people treated with CTLA-4 inhibitors or PD-1 inhibitors and includes a wide range of different types; these require early referral to a cardiologist and treatment with high-dose corticosteroids or other immunosuppressive drugs. If you have any questions or concerns, or notice any worrying symptoms (or worsening of existing symptoms), you should inform your doctor or oncology team as soon as possible so they can address these promptly and give you the best possible care. Remember that most side effects to checkpoint inhibitors are mild and reversible if detected early, so the most important thing is to tell your doctor or oncology team about any symptoms that concern you. 24

25 ESMO Patients Guide References Boutros C, Tarhini A, Routier E, et al. Safety profiles of anti-ctla-4 and anti-pd-1 antibodies alone and in combination. Nat Rev Clin Oncol 2016;13(8): Champiat S, Lambotte O, Barreau E, et al. Management of immune checkpoint blockade dysimmune toxicities: a collaborative position paper. Ann Oncol 2016;27(4): Haanen JBAG, Carbonnel F, Robert C, et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2017;28(suppl_4):iv119-iv142. June CH, Warshauer JT, Bluestone JA. Is autoimmunity the Achilles heel of cancer immunotherapy? Nat Med 2017;23(5): Kamta J, Chaar M, Ande A, Altomare DA, Ait-Oudhia S. Advancing Cancer Therapy with Present and Emerging Immuno-Oncology Approaches. Front Oncol 2017;7:64. 25

26 Immunotherapy-related side effects GLOSSARY ACQUIRED IMMUNITY The aspect of the body s immune response that is learned from encountering foreign antigens ACTIVE IMMUNOTHERAPY A type of immunotherapy that stimulates the person s immune system to respond to one or more antigens by producing antibodies, e.g. a vaccine ANAEMIA A condition characterised by the shortage of red blood cells or haemoglobin (a protein in red blood cells that carries oxygen around the body) ANTIBIOTICS Drugs that fight bacterial infections ANTIBODY A blood protein produced in response to, and able to counteract, a specific antigen ANTI-DIARRHOEAL A medication that provides symptomatic relief from diarrhoea ANTIGEN A molecule capable of inducing an immune response ANTIGEN-PRESENTING CELL Any cell that can ingest and present an antigen to an immune cell in a form it recognises and responds to ANTIHISTAMINE A type of drug used to treat allergies ATEZOLIZUMAB A type of immunotherapy that blocks the interaction between PD-L1 and PD-1 on the surface of certain immune cells called T cells; this activates T cells to find and kill cancer cells. Atezolizumab is a monoclonal antibody. It is administered through a drip into a vein in your arm or chest AUTOIMMUNITY An immune response against the body s own healthy cells and tissues AVELUMAB A type of immunotherapy that blocks the interaction between PD-L1 and PD-1 on the surface of certain immune cells called T cells; this activates T cells to find and kill cancer cells. Avelumab is a monoclonal antibody. It is administered through a drip into a vein in your arm or chest B CELL A type of white blood cell, or lymphocyte, that produces antibodies BACTERIA Microscopic single-celled organisms, some of which are capable of causing infection BETA-BLOCKERS Drugs that slow the heart rate and lower blood pressure BONE MARROW A spongy tissue found inside some bones (e.g. hip and thigh bones). It contains stem cells, which are cells that can develop into the red blood cells, white blood cells or platelets BRONCHOSCOPY A procedure by which a doctor inserts a special device into the main breathing tube (bronchus), usually via the nose or mouth, to examine the airways (including the lungs) BSA Body surface area; the measurement of the surface area of the body CARDIAC Relating to the heart CARDIOLOGIST A doctor who specialises in diseases and abnormalities of the heart CHECKPOINT INHIBITOR A type of drug that blocks certain immune responseinhibiting proteins made by immune system cells, such as T cells, and some cancer cells and thus enhances the body s immune response CHEMOTHERAPY A type of cancer treatment using medicine that kills the cancer cells by damaging them, so that they cannot reproduce and spread CLINICAL TRIAL A study that evaluates the effects of a medical treatment or intervention COLITIS Inflammation of the colon or large intestine COLON Large intestine 26

27 ESMO Patients Guide GLOSSARY COLONOSCOPY A procedure in which a flexible instrument is inserted into the anus (back passage) in order to examine the colon CONSTIPATION Difficulty emptying the bowels, usually associated with hardened faeces CORNEA The transparent layer forming the front of the eye CORTICOSTEROID A type of steroid drug used to relieve inflammation CT SCAN Computed tomography; a scan using x-rays and a computer to create detailed images of the inside of your body CTLA-4 A special protein molecule that, functioning as an immune checkpoint, turns down an immune response once it has done its job CTLA-4 INHIBITOR A type of drug that blocks the CTLA-4 immune checkpoint on the surface of certain immune cells called T cells; this activates T cells to find and kill cancer cells, thereby enhancing the immune response CYTOTOXIC T CELL A type of white blood cell, or lymphocyte, able to kill infected or cancer cells DERMATOLOGIST A doctor who specialises in diseases of the skin DIARRHOEA Abnormal frequency of loose or liquid stools (faeces) DURVALUMAB A type of immunotherapy that blocks the interaction between PD-L1 and PD-1 on the surface of certain immune cells called T cells; this activates T cells to find and kill cancer cells. Durvalumab is a monoclonal antibody. It is administered through a drip into a vein in your arm or chest ELECTROLYTE A substance (e.g. sodium or calcium) that regulates the flow of nutrients into, and waste products out of, cells ENDOCRINE Relating to glands that secrete hormones into the bloodstream FATIGUE Overwhelming tiredness FUNGI Microscopic organisms some of which are capable of causing infection GASTROINTESTINAL Relating to stomach and intestines GASTROINTESTINAL TRACT The digestive tract, comprising a large muscular tube extending from the mouth to the anus (back passage) via the stomach that is responsible for digesting food and expelling waste products as stools (faeces) HAIR FOLLICLE A small sac in the skin from which hair grows from HEPATITIS Inflammation of the liver HORMONE A chemical messenger produced by a specialised gland in the body HYPERTHYROIDISM Overactivity of the thyroid gland HYPOPHYSITIS Inflammation of the pituitary gland (located in the brain) HYPOTHYROIDISM Underactivity of the thyroid gland IMMUNE CELL A cell involved in an immune response or forming part of the immune system IMMUNE CHECKPOINT A molecule in the immune system that either turns up a signal (enhances the immune response) or turns down a signal (decreases the immune response) IMMUNE RESPONSE The reaction of cells and fluids of the body to the presence of a substance which is not recognised as a part of the body itself IMMUNE SYSTEM The system in the body that works to ward off infection and disease IMMUNO-ONCOLOGICAL Relating to immuno-oncology (next page) 27

28 Immunotherapy-related side effects GLOSSARY IMMUNO-ONCOLOGY The discipline in medicine that uses strategies harnessing the immune system to treat cancer IMMUNOSUPPRESSIVE Drugs or other factors that partially or completely suppressing the immune response IMMUNOTHERAPY The prevention or treatment of disease with substances that stimulate (or suppress) the immune response INFLIXIMAB A type of drug called a monoclonal antibody that is used to treat autoimmune diseases INNATE IMMUNITY A non-specific type of immunity that humans are born with and which does not require a learning process or prior exposure to an antigen INTRAVENOUS Administered into a vein IPILIMUMAB A type of immunotherapy that blocks the CTLA-4 immune checkpoint on the surface of certain immune cells called T cells; this activates T cells to find and kill cancer cells. Ipilimumab is a monoclonal antibody. It is administered through a drip into a vein in your arm LEUCOCYTE A white blood cell involved in the immune response LEUCOPAENIA A decrease in the number of leucocytes (a type of white blood cell) in the blood, which places individuals at increased risk of infection LOPERAMIDE A drug used to treat diarrhoea LYMPHATIC SYSTEM The network of vessels through which a clear fluid called lymph drains from the tissues into the blood; it is a vital part of the immune system LYMPHOCYTE A type of white blood cell LYMPHOID Relating to cells, tissues and organs that make up the lymphatic system MAJOR HISTOCOMPATIBILITY COMPLEX A group of protein molecules on the surface of cells that enable the immune system to differentiate self from non-self MALIGNANT Malignant is another term for cancerous. Malignant cells can invade nearby tissue and spread to other parts of the body MEMORY CELL A long-lived lymphocyte capable of remembering and responding to a particular antigen the next time it encounters it MICROORGANISM A microscopic organism (e.g. a virus) MOLECULE The smallest physical unit of a substance MONOCLONAL ANTIBODY A type of targeted therapy. Monoclonal antibodies recognise and attach to specific proteins produced by cells. Each monoclonal antibody recognises one particular protein. They work in different ways depending on the protein they are targeting MUCOSITIS The painful inflammation and ulceration of the mucous membranes lining the digestive tract MUTATED Relating to a permanent alteration in the DNA sequence that makes up a gene, such that the sequence differs from what is found in most people NAUSEA A feeling of sickness with an urge to vomit (be sick) NEUROLOGICAL Relating to any aspect of the nervous system NEUTROPAENIA An abnormally low level of neutrophils in the blood, which increases risk of infection NIVOLUMAB A type of immunotherapy that blocks a protein called PD-1 on the surface of certain immune cells called T cells; this activates the T cells to find and kill cancer cells. Nivolumab is a monoclonal antibody. It is administered through a drip into a vein in your arm or chest ORAL By mouth 28